期刊
ACS INFECTIOUS DISEASES
卷 7, 期 5, 页码 1200-1207出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.0c00803
关键词
Cryptosporidium; cryptosporidiosis; bumped kinase inhibitors; pyrrolopyrimidines; pyrazolopyrimidines
资金
- US Department of Veterans Affairs Biomedical Laboratory Research and Career Development Award [BX002440]
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [R21AI123690, R01AI089441, R01AI111341, R01A1112427, R01HD080670]
- US Department of Agriculture, National Institute of Food and Agriculture [2014-06183]
The study explored two pyrrolopyrimidines and showed improved potency over the previously utilized pyrazolopyrimidine bumped kinase inhibitors in multiple models while maintaining equivalent results in other key properties with their pyrazolopyrimidine isosteric counterparts.
Bumped kinase inhibitors (BKIs) that target Cryptosporidium parvum calcium-dependent protein kinase 1 have been well established as potential drug candidates against cryptosporidiosis. Recently, BKI-1649, with a 7H-pyrrolo[2,3-d]pyrimidin-4-amine, or pyrrolopyrimidine, central scaffold, has shown improved efficacy in mouse models of Cryptosporidium at substantially reduced doses compared to previously explored analogs of the pyrazolopyrimidine scaffold. Here, two pyrrolopyrimidines with varied substituent groups, BKI-1812 and BKI-1814, were explored in several in vitro and in vivo models and show improvements in potency over the previously utilized pyrazolopyrimidine bumped kinase inhibitors while maintaining equivalent results in other key properties, such as toxicity and efficacy, with their pyrazolopyrimidine isosteric counterparts.
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